A combination vaccine approach utilizing adenovirus-HIV or SIV-recombinants to prime immune responses followed by boosting with subunit protein elicits humoral, cellular, and mucosal immune responses in non-human primates. Significant protection against infection and/or disease progression has been demonstrated in chimpanzee and macaque models. These results have provided the basis for moving the strategy forward into human phase I trials. To further develop the approach, mutational analyses have been performed to identify deleterious sequences while preserving immunogenic epitopes in target genes. New adenovirus recombinants have been constructed and a broader spectrum of HIV and SIV structural, regulatory, and auxilliary genes are being incorporated into the adenovirus vectors. These will be assessed in appropriate animal models in combination with DNA immunizations for synergistic priming. The booster subunit immunogen has also been a focus of investigations. A novel, synthetic peptide polymer (peptomer) representing the binding site for CD4 on the viral envelope, mimics the native structure of the protein. As the peptomer contains CTL, T-helper, and conformational B-cell epitopes, it should elicit good immunity and exhibit protective efficacy against a broad spectrum of viral isolates. Evaluation of an SIV peptomer in macaques has shown that it is very immunogenic but not protective. Viral isolates which emerged following the challenge exposure were CD4 independent, suggesting immune selection of viral escape mutants. Further studies will be necessary to determine if the CD4 binding domain of the envelope should be eliminated from vaccine preparations, or if the strategy will prove effective in the HIV system, which is less prone to development of CD4 independent isolates. Finally, an effective vaccine must prevent sexual transmission of HIV, and studies have focused on protective immune responses at mucosal sites. Natural resistance in a macaque has been shown to result from viral-specific cellular immunity acquired following previous mucosal SIV exposures which did not result in infection. The mechanism responsible for the initial resistance appears to involve regulation of CCR5 expression on the surface of macaque CD4+ T cells following viral infection, resulting in a failure of viral amplification. These studies have also pointed to the lamina propria of the intestine as a potential viral reservoir. AIDS title: Adenovirus-Recombinant/Subunit Protein Vaccines for AIDS.